α1-Adrenergic Receptors: Insights into Potential Therapeutic Opportunities for COVID-19, Heart Failure, and Alzheimer’s Disease

α1-Adrenergic receptors (ARs) are members of the G-Protein Coupled Receptor superfamily and with other related receptors (β and α2), they are involved in regulating the sympathetic nervous system through binding and activation by norepinephrine and epinephrine. Traditionally, α1-AR antagonists were first used as anti-hypertensives, as α1-AR activation increases vasoconstriction, but they are not a first-line use at present. The current usage of α1-AR antagonists increases urinary flow in benign prostatic hyperplasia. α1-AR agonists are used in septic shock, but the increased blood pressure response limits use for other conditions. However, with the advent of genetic-based animal models of the subtypes, drug design of highly selective ligands, scientists have discovered potentially newer uses for both agonists and antagonists of the α1-AR. In this review, we highlight newer treatment potential for α1A-AR agonists (heart failure, ischemia, and Alzheimer’s disease) and non-selective α1-AR antagonists (COVID-19/SARS, Parkinson’s disease, and posttraumatic stress disorder). While the studies reviewed here are still preclinical in cell lines and rodent disease models or have undergone initial clinical trials, potential therapeutics discussed here should not be used for non-approved conditions.


Introduction
Receptors that are activated by the adrenaline-type catecholamines, epinephrine (Epi) and norepinephrine (NE), are called adrenergic receptors (ARs). They belong to the G-Protein Coupled Receptor (GPCR) superfamily, which are receptors that transduce their intracellular signals through G-proteins. According to their physiological effects on the body, they were initially assigned as classifications α and β [1]. α-ARs were later further subdivided into α 1 -and α 2 -ARs, after noting that some functions were distinctively different between the two families. Upon further tissue characterization and molecular cloning, α 1 -ARs were further subdivided into the α 1A -, α 1B -AR, and α 1D -AR subtypes based upon the subsequent cloning of the receptors [2][3][4]. The α 1C -AR is missing from the current α 1 -AR nomenclature due to misclassification and incomplete pharmacological characterization of the α 1A -AR subtype [4,5].
5. α 1A -AR Agonists 5.1. Currently Approved Uses α 1 -AR agonists are not commonly prescribed because of the potential to raise blood pressure but are approved for the treatment of vasodilatory shock, hypotension, hypoperfusion, septic and refractory shock, and cardiopulmonary arrest. Approximately 7% of critically ill patients develop refractory shock causing a 50% short-term mortality rate [41]. Vasopressor agents used to maintain blood pressure and preserve tissue perfusion during shock are methoxamine (discontinued in the US) or norepinephrine/epinephrine [42,43]. α 1 -AR agonists such as phenylephrine have been used in procedures to dilate the iris [44]. Phenylephrine, naphazoline, and oxymetazoline are also used in nasal decongestion and edema [45,46] and the facial erythema associated with rosacea [47,48].

Heart Failure and Cardioprotection
The human heart contains both the α 1A and α 1B -AR subtypes with a total density of approximately 11-60 fmoles [49][50][51]. The α 1D -AR may be present in the myocyte but at very low levels [52,53]. The current hypothesis is that selective α 1A -AR agonists may be a potential treatment in heart failure [54,55], since chronic α 1B -AR stimulation, as evidenced through transgenic mouse models, appears to be maladaptive by inducing dilated cardiomyopathy [29] or heart failure [37]. While α-AR blockers are a current treatment option for heart failure, using α 1A -AR selective agonists may provide potentially greater benefits such as preventing dementia [56], improving metabolic function and glucose tolerance [56][57][58], increasing lifespan with reduce cancer risk [59,60] and reducing inflammation and cataracts [58,61].
The preclinical evidence that the α 1A -AR subtype is cardioprotective and could be therapeutic for heart failure is abundant. Transgenic mice with heart-targeted α 1A -AR overexpression were protected from dysfunction due to myocardial infarction [26], pressureoverload [25], or imparted ischemic preconditioning [34,62]. Correspondingly, α 1A -AR KO mice had induced greater heart injury after myocardial infarction [55]. The α 1A -AR selective agonists, A61603 or dabuzalgron, prevented damage from the cardiotoxic agent, doxorubicin [63][64][65] and increased contraction during heart failure [66]. Removing load by mechanical assist devices in failing human hearts improved function and re-distributed α 1A -ARs from the peri-to intra-myocyte location [67]. However, there are currently no clinical trials underway, most likely due to the potential to increase blood pressure and the risk of stroke. The use of positive allosteric modulators (PAMs) for the α 1A -AR developed to treat Alzheimer's disease [12] are currently in preclinical studies in mice and to assess potential benefits in heart failure.
The ability of the α 1A -and not the α 1B -AR to cardioprotect may be due to several mechanisms. One is the ability of the α 1A -AR to increase inotropy [30, 68,69]. Another mechanism may be due to increased glucose uptake and oxidation in the heart [70] as glucose oxidation has been shown to repair heart damage after ischemia or heart failure [71][72][73][74][75][76]. Transgenic α 1A -but not α 1B -AR mice increased glucose uptake into the heart and only the α 1A -AR KO mice displayed decreased glucose uptake into the heart [57]. Heart failure has been described as a metabolic disease of energy starvation [77] and so any therapeutic that can increase ATP production may improve heart function.

Cognition and Memory
α 1 -ARs have long been associated with learning and memory functions [7]. α 1 -AR agonists promoted while α 1 -AR antagonists blocked long-term potentiation (LTP, a mechanism of memory formation) in the rat CA1 hippocampus [78], neocortex [79], and may coordinate with β-AR signaling [80][81][82][83]. α 1A -AR systemically overexpressing transgenic mice increased synaptic plasticity, LTP, and performance in a battery of cognitive tests of spatial memory, while α 1A -AR KO mice performed poorly [60]. α 1B -AR KO mice had impaired spatial learning to novelty and exploration [84], and a decrease in memory consolidation and fear-motivated exploration [85]. While α 1D -AR KO mice did not show deficits in spatial learning [86], they did show deficits in working memory and attention [87]. While all three α 1 -AR subtypes are localized in the brain and expressed in overlapping domains, the α 1A -AR subtype appears to have greater expression in cognitive areas such as the hippocampus and amygdala, as well as particular areas of the cortex and neurogenic regions involved in learning and memory [88,89]. The α 1A -AR selective agonist cirazoline increased cognition and BrdU incorporation in normal adult mice, while the α 1A -AR overexpressing transgenic mice had increased BrdU incorporation in both the subventricular and subgranular neurogenic regions [88].
In order to develop suitable therapeutic α 1A -AR agonists to treat heart failure, cardiac ischemia, or Alzheimer's disease, PAMs with sufficient signal bias would need to be developed that could regulate heart or brain function without effects on the vascular system to increase blood pressure. PAMs will increase a receptor activation and function but in such a way that it does not bind to the same site as the endogenous agonist (i.e., orthosteric), such as NE [90]. Allosteric modulators result in decreased side effects and have greater selectivity by binding to non-conserved regions of the receptor resulting in conformational bias that can alter the receptor's signaling pathways. There are now many GPCR allosteric modulators in clinical trials [91]. Another issue is the poor brain penetration of most of the current α 1 -AR agonists which limit their use in neurological conditions. The first PAM at the α 1 -ARs with high selectivity for the α 1A -AR subtype has been developed [12] that can cross the blood-brain barrier sufficiently enough to improve cognitive functions and modify disease in Alzheimer's disease mouse models without increased blood pressure. This drug (i.e., Cmpd-3, Table 1) only activates the NE-bound receptor and can potentiate cAMP signaling without effects on IP-signaling. IP-signaling and the resulting calcium release causes the increase in blood pressure. However, NEmediated cAMP signaling in the brain regulates learning and memory [92][93][94][95][96][97]. This drug is currently in preclinical studies to treat heart failure.

Currently Approved Uses
As in the vascular system, α 1 -AR antagonists affect the contraction of smooth muscle in several organ systems. α 1 -AR blockage results in the relaxation of smooth muscle in the prostate and ureter to increase urinary flow [98][99][100]. Since the 1980s and 1990s, α 1 -AR antagonists are frequently used medications in the management of benign prostatic hyperplasia (BPH), kidney stones, and in therapy-resistant arterial hypertension, two conditions frequently found in older adults. As a powerful anti-hypertensive, α 1 -AR antagonists are not recommended as a first-line treatment [101,102] as they are counter indicative for those with heart disease. While α 1 -AR antagonists are effective in the relief of urinary symptoms and improve the quality of life in BPH, they appear less effective in preventing disease progression [103,104]. α 1 -AR blockers are also used to treat pheochromocytoma, a rare condition where a tumor forms on the adrenal gland or other paraganglia to cause excessive catecholamine release and severe hypertension. The tumor is excised immediately under the use of an α 1 -AR blocker to reduce hemodynamic instability, morbidity and mortality [105]. General counterindications for α 1 -AR antagonists will be discussed at the end of this article.

COVID-19/SARS
Coronavirus disease 2019 (COVID-19) and the causative agent, severe acute respiratory syndrome coronavirus 2 (SARS), can elicit a vigorous systemic immune response (i.e., hyperinflammation) in the lungs as well as multiple organs, resulting in heart and kidney failure, liver damage, precipitating severe illness, and increased mortality [106]. Recent evidence suggests that some patients with COVID-19 develop a cytokine storm syndrome that is associated with increased release of pro-inflammatory cytokines, disease severity, and poor clinical outcomes [107].
Beyond their role in neurotransmission, cardiovascular, and the stress response, α 1 -ARs have been shown to modulate the immune system [108,109], innate immunity [110], and inflammatory damage by increasing cytokine production in immune cells [111,112]. α 1 -ARs have been identified on a wide variety of immune cells. Identification of immune cells using flow cytometry depends upon highly avid antibodies whose specificity are questioned for the current commercially available antibodies for the α 1 -ARs and many other GPCRs [113]. However, many studies have utilized mRNA expression and ligand binding analysis. Human neutrophils contain the mRNA for all three α 1 -AR subtypes [114]. Monocytes contain the mRNA for the α 1B -and α 1D -ARs [112,115,116]. NK killer cells, leukocytes [117][118][119], and lymphocytes, including human peripheral blood lymphocytes [120,121], also contain α 1 -ARs but the subtypes are not clearly defined.

α 1 -AR Antagonists May Protect against Severe COVID-19
Several studies indicate that α 1 -AR antagonists may reduce morbidity and mortality in patients at risk for hyperinflammation and cytokine storm that is often associated with COVID-19 and other conditions that result in severe respiratory tract conditions. Blockade of α 1 -AR function with prazosin prevents cytokine storm following pro-inflammatory conditions and increases survival in preclinical studies [122]. A retrospective analysis in two large cohorts of patients with acute respiratory distress (n = 18,547) and three cohorts with pneumonia (n = 400,907) found that patients exposed to α 1 -AR antagonists had a significantly lower risk (34%) for mechanical ventilation and death [123]. Similar results were obtained in a subsequent retrospective analysis on US veterans [124] and another large cohort study of influenza or pneumonia patients in Denmark [125]. These studies led to a clinical trial to test whether prazosin can prevent the cytokine storm syndrome [126] caused by COVID-19 (https://clinicaltrials.gov/ct2/show/NCT04365257, accessed on 7 February 2023) but this trial is currently halted due to lack of recruitment. These results extend circumstantial findings that prazosin may be an early preemptive therapy in COVID-19 and may prevent the cytokine storm and severe complications due to hyperinflammation.

α 1 -AR Antagonists May Not Prevent COVID-19 Infection
The protective effects of α 1 -AR blockers against COVID-19 were recently challenged in a study using meta-analysis of millions of patients prescribed α 1 -AR blockers (alfuzosin, doxazosin, prazosin, silodosin, tamsulosin, and terazosin), compared to alternative medications (dutasteride, finasteride, and 5-α-reductase inhibitors) or tadalafil (PDE5 inhibitor) to treat BPH. This study found no reduction in the risk of COVID-19 infection due to the sustained use of α 1 -AR blockers [127]. The negative results are unlikely due to the comparison to non-α 1 -AR blocker treatments for BPH as the study of Thomsen et al. [125] also included non-users (normal controls). However, this study did find significant but not large differences on the ability of α 1 -AR blockers to confer protective benefits against death and ICU admission due to COVID-19.
The study of Nishimura et al. [127] suggested that previous positive results from clinical trials had systematic biases from residual confounding [128,129]. For example, patients with severe asthma are more likely to be prescribed α-agonists and to die from their asthma than patients with less severe disease but not receiving treatment. Therefore, such confounding would make α-agonists appear they were associated with asthma mortality. However, all epidemiology studies that utilize user vs. non-user comparisons from databases are prone to systematic biases from residual confounding. The study of Nishimura et al. [127] used a database of older male patients that are at higher-risk for COVID-19 and for developing severe COVID-19 compared to the general population, and then analyzed the risks of developing COVID-19, being hospitalized, or hospitalizations that also require intensive services requiring ventilation or oxygenation. The study of Thomsen et al. [125] and others, while also analyzing older men, used a database of high-risk patients already hospitalized with hyperinflammation or cytokine storm (pneumonia, severe COVID, and influenza) and measured α 1 -AR blocker effects on more severe outcomes (ICU, mortality). Therefore, one interpretation is that α 1 -AR blockers do confer protection, but the amount of pre-emptive protection is not that significant for use in the general population but only for a subset of severely ill patients once the cytokine storm has developed, and then used to reduce mortality. All of these studies have limitations in that they measured outcomes on men who are more likely to be prescribed α 1 -AR blockers due to BPH and may not reflect possible outcomes for women. Nevertheless, these results suggest the need for further clinical trials to include women and whether α 1 -AR blockers first ameliorates the severe symptoms of lower respiratory tract infection-associated hyperinflammation and the risk of death.

The Case for Anti-Hyperinflammation as a Direct α 1 -AR Mediated Effect
There is precedent in preclinical studies for the ability of α 1 -AR blockers to reduce hyperinflammation. Prazosin prevents cerebral infarction by inhibition of the inflammatory cascade [130]. One mechanism that α 1 -ARs may use to combat hyperinflammation is through their association with chemokine receptors. Chemokines are a group within the cytokine family whose general function is to induce cell migration and are potential therapeutic targets in numerous inflammatory diseases, such as COVID-19. Several chemokine genes have been associated with disease severity and susceptibility to infection with COVID-19 [131]. At least 20 members of the human chemokine receptor family heterodimerize with the α 1B or α 1D -AR subtypes and inhibited their function and were detectable in human monocytes [118]. The CXCR2 has been reported to heterodimerize with the α 1A -AR in prostatic smooth muscle [132]. Many GPCRs can form homo-and hetero-oligomers, which is thought to alter their pharmacological behavior and function and may play a role in pathophysiology [133][134][135]. Another mechanism that is described is through catecholamine excess [136]. In animal studies, the blockade of catecholamine synthesis (and indirect blockage of α 1 -ARs) reduced cytokine release and protected mice against COVID-19 lethal complications [122]. Furthermore, autoantibodies against GPCRs, including the α 1 -AR, were observed in patients after SARS infection and suggested to cause impaired blood flow, the formation of microclots, and autoimmune dysfunction contributing to long-COVID symptoms [137,138]. These results suggest a direct effect of α 1 -AR antagonists in blocking α 1 -AR mediated adverse effects in hyperinflammation.

The Case for Non-α 1 -AR Mediated Effects of Quinazoline Antagonists: PGK1
It is possible that the protective anti-inflammatory effects of prazosin, doxazosin and terazosin may be non-α 1 -AR mediated through activation of phosphoglycerate kinase (PGK1)-mediated ATP production. Terazosin and its related "osins" are postulated to mediate protective mechanisms by binding adjacent to the ADP-ATP site of PKG1 and facilitating its activation. PGK1 is the first enzyme in glycolysis where ADP enters the cleft of the active site and is converted into ATP and shown to inhibit apoptosis [139,140]. Terazosin increases the release of ATP by competing for the same binding site, re-exposing the binding pocket, thereby exerting an agonistic effect [140]. PKG1 binding and activation has also been demonstrated in related α 1 -AR antagonists that contain quinazoline motifs, such as alfuzosin, prazosin, and doxazosin [140]. PGK1 activation may improve cellular functions in disorders with an established energy deficit, common with critically ill patients [141] and COVID-19 patients [142,143]. Terazosin was shown to increase PGK1 activity and glycolysis in motor neuron models of amyotrophic lateral sclerosis (ALS), which correlated with protection and survival [144]. The effects of prazosin-like compounds appear directed at the quinazoline structural motif, as tamulosin, also an α 1 -AR blocker but with some selectivity for the α 1A -AR [145], does not appear to mediate anti-inflammatory effects, does not contain the quinazoline motif, and does not interact with PGK1 [139,146]. Furthermore, an analysis of the Truven database and Danish nationwide health registries demonstrated that individuals treated with terazosin, alfuzosin, or doxazosin showed lower rates of Parkinson's disease (PD) and PD-related diagnoses when compared with patients treated with tamsulosin [147]. Therefore, quinazoline-based antagonists of the α 1 -ARs may confer therapeutic levels of protection against inflammation and morbidity through non-α 1 -AR -mediated effects of increasing glucose metabolism by binding to the active site of PGK1.
While the above protective effects of PGK1 appear to be metabolic, α 1 -AR quinazolines (i.e., not tamsulosin) have also been shown in several studies to induce apoptosis in different cell lines and in vivo through non-α 1 -AR mechanisms [148][149][150]. Pyroptosis, a proinflammatory form of apoptosis, acts as a host defense mechanism against infections. Pyroptosis decreases the replicative ability of viruses by inducing the apoptosis of infected cells and exposing the virus to extracellular immune defenses. Several therapeutics that target inflammasomes, caspases, or cytokines are in clinical trials to evaluate efficacy in mitigating the severe outcomes of COVID-19 [151]. Therefore, the ability to reduce severity of COVID-19 outcomes by prazosin and other quinazolines may be due to their ability to increase apoptosis, improve energy deficit, or both.
These two different but protective mechanisms (metabolic verses apoptotic) may be cell-type, α 1 -AR subtype, or disease-dependent. All of the pro-apoptotic effects of quinazolines are non-α 1 -AR mediated and mostly found in cancer cell lines, while metabolic effects are more systematic and may be α 1 -AR subtype dependent. The non-quinazoline tamsulosin does not exhibit cytotoxic or apoptotic activity in cancer cell lines [148]. Prazosin treatment protects the brain by decreasing oxidative stress and apoptotic pathways [152]. A non-quinazoline α 1 -AR antagonist reduced inflammation and immune cell infiltration and improved insulin signaling in the adipose of fructose-fed rats [153], as well as cardiac, vascular, and renal dysfunction in hypertensive rats [154].

α 1A -AR Activation but α 1B -AR Blockage Is Protective
Concerning α 1 -AR subtype-dependent effects of antagonists, there is evidence that α 1A -AR activation is protective, while chronic α 1B -AR activation is damaging and neurodegenerative. Therefore, α 1A -AR agonists would be protective and in systems where chronic α 1B -AR activation is damaging, non-selective blockers may exert protective effects. Systemic overexpression of the α 1A -AR in mice has anti-tumor effects [59], preconditions the heart against ischemia [34], reverses heart failure and cardiac apoptosis [62,65,66], and increases longevity [59]. In contrast, systemic overexpression of the α 1B -AR subtype in mice was neurogenerative, induced autonomic dysfunction, heart failure, apoptosis [37, 38,155,156], and decreased lifespan [59]. Tamsulosin has a 10-fold higher binding affinity and slower dissociation kinetics compared to the other two subtypes, rendering it an α 1A -AR selective antagonist [145,157]. The epidemiology study of [158], while finding that usage of terazosin/alfuzosin/doxazosin failed to see any changes in the risk in Parkinson's disease (PD) development, did find that tamulosin increased PD risk and may associate with disease progression. Protective effects of prazosin may be due to α 1B -AR blockage since tamsulosin (α 1A -AR blockage) does not induce apoptosis nor binds with PGK1. The study of Koenecke (2021) [123] found that doxazosin was two-fold more efficacious than tamsulosin in preventing COVID mortality, suggesting blockage of α 1B or α 1D -mediated pro-inflammatory effects. There is an increased expression and cellular proliferation of the α 1B -AR subtype in prostatic cancer cell lines that exhibit apoptosis with prazosin [159]. α 1B -AR activation mediates unchecked cell cycle progression and induced foci formation [160], supporting a cancer-inducing paradigm. Therefore, protective effects of α 1 -AR blockage might indicate that the α 1B -or α 1D -AR subtype is being blocked in the particular tissue or disease.

Other Neurological Benefits of α 1 -AR Quinazoline Antagonists: Parkinson's, ALS, PTSD
Neuroprotection, just like cardioprotection, may be mediated through increased metabolism [161]. As the heart is energy-starved during failure, so too are several neurodegenerative diseases. Glucose metabolism is essential for proper brain function, accounting for 20% of whole-body energy consumption, but compiles only 2% of body mass. Therefore, brain energy demand is mostly met by the metabolism of glucose [162]. Bioenergetic and mitochondrial dysfunction are common hallmarks of PD and ALS, and regulate disease onset and progression [161,163,164]. In ALS pathogenesis, the early dysregulation of the AMPK signaling pathway was found in motor neurons and in a large proportion of patients [165]. Preclinical and epidemiologic data suggest that terazosin, a quinazoline antagonist, may be neuroprotective in PD and ALS [144,166] and impart a decreased risk for developing PD [139]. However, another study that analyzed a large database of terazosin/alfuzosin/doxazosin users failed to see any changes in the risk of PD development [158]. A clinical study evaluating the safety and tolerability of terazosin, 5 mg once daily for 12 weeks, in patients with PD has been initiated (NCT03905811). Doxazosin can also reduce oxidative stress, pro-inflammatory cytokines, and cell death in rat photoreceptor cells in vivo [167]. Terazosin protected against organ damage, sepsis, and death in rodent models [140]. Therefore, nonselective α 1 -AR quinazoline antagonists may also be useful in other neurodegenerative diseases.
Posttraumatic stress disorder (PTSD) is associated with elevated noradrenergic activity [168][169][170]. In clinical trials and meta-analysis, prazosin has been effective and well-tolerated to reduce combat trauma nightmares, sleep disorders, and general clinical status in veterans [171][172][173] and for general trauma-related nightmares [174]. Compared with image rehearsal therapy which is the recommended treatment for trauma-induced nightmares, prazosin was more efficacious at relieving the frequency and stress-related symptoms but image rehearsal therapy combined with cognitive behavioral therapy was better at improving sleep quality [175]. A more recent study by Raskind et al. (2018) [176] also showed that prazosin did not improve sleep-related problems in PTSD. However, it is unclear whether or not prazosin will reduce the risk of nightmares in people without trauma or whether other α 1 -AR blockers (non-quinazolines) are effective. α 1A -AR stimulation has been suggested to mediate stress-induced memory formation and consolidation [7] and, therefore, blockage with prazosin may be psychotherapeutic, resulting from a direct α 1A -AR antagonistic effect.

α 1A -AR Blockers but Not Non-Selective Antagonists May Increase Dementia and Depression
While non-selective α 1 -AR quinazoline antagonists appear to improve symptoms in neurodegenerative diseases and PTSD, regardless of whether they are α 1 -AR or non-α 1 -AR mediated, antagonists that are selective for the α 1A -AR subtype may potentiate neurodegeneration and dementia. This would be consistent with α 1A -AR activation demonstrating increased cognitive performance and reversing Alzheimer's disease as discussed in this review. Just as tamsulosin does not follow the protective properties of quinazoline antagonists as discussed in the above sections, tamsulosin, which is α 1A -AR selective, increases the risk of dementia modestly and other adverse cognitive effects, in particular among patients over age 61 [177]. This study utilized cohorts taking various medications (including 5a-reductase and quinazoline α 1 -AR blockers) for BPH as well as those taking no medications and followed them for 20 months after the first prescription was filled. However, two subsequent clinical studies contradict these results [178,179]. While tamsulosin did increase the risk of dementia, there was no evidence of a dose-response, and after adjustments for confounding variables, the results were not significant [179]. Differences between the three studies could be due to the mean age that was assessed. The two negative studies used a mean age of 78.7 [178], and 76.1 years [179], while the positive study of Duan et al. (2018) [177] used younger patients for a mean age of 73.2. As the risk of cognitive decline increases dramatically with age [180,181] or genetic variant status (APOE e4) [182], the amount of baseline neurodegeneration may have been substantially different in the two studies to mask any benefit. The study of Tae et al. (2019) [179] acknowledged that age was the strongest variable in the risk of dementia in all their comparisons. Another variable is the length of follow up. The positive study followed patients for 20 months [177], while the other two negative studies followed patients for 56 months [179] and 36 months [178]. Again, the two negative studies would have increased dementia at study end given the advanced age of the patients.
The amygdala can regulate psychological stressors and anxiety, besides regulating fearconditioned memory and memory consolidation [7,183], and is regulated by the α 1A -AR subtype [89,184]. Transgenic mice overexpressing the α 1A -AR but not the α 1B -AR showed antidepressant behavior [185]. α 1A -AR blockage with WB4101 induces learned despair in mice [186] and tamsulosin facilitated depressive-like behavior in mice [187]. While a small clinical study found that tamsulosin decreased patient-reported depressive symptoms in BPH patients, contrary to the hypothesized effect in mice [188], BPH itself is associated with increased depressive and anxiety symptoms [189,190] and suicide [191]. Further large-scale clinical studies are needed to determine if tamsulosin and other α 1A -AR blockers may increase depressive and anxiety-based disorders as hypothesized.

α 1 -AR Blockers May Increase Risk of Heart Failure
The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) is a large, randomized double-blind study comparing four different classes of antihypertensive agents in patients older than 55 years [101]. The use of doxazosin (i.e., Cardura) increased the risk of stroke and the development of heart failure twice as much as those receiving a thiazide diuretic and caused this arm of the study to terminate early. In addition, doxazosin is not recommended as a first-line antihypertensive, particularly in the elderly [101,103]. However, this effect is not just isolated to doxazosin. A recent study of 175,200 men with BPH treated with either 5-alpha reductase inhibitors, various α 1 -AR antagonists, or a combination, found a 22% increased risk of cardiac failure among the users of α 1 -AR blockers [192]. Non-selective α 1 -AR blockers (terazosin, doxazosin, and alfuzosin) were significantly associated with an 8% higher risk for heart failure compared with selective α 1A -AR blockers (silodosin and tamsulosin). Silodosin is 500-fold more selective for the α 1A -AR than α 1B -AR [193], while tamsulosin is 10-fold selective [145]. The α 1A -AR is theorized to be cardioprotective and agonists protect against heart failure [56], but why are α 1A -AR blockers then not associated with a higher risk of heart failure compared to non-selective blockers? There may be other non-α 1 -AR mediated effects associated with the increased risk of heart failure, such as increased apoptosis [148][149][150], particularly with α 1 -AR quinazoline blockers. While α 1 -AR blockers are still a popular treatment for BPH, and particularly in younger men who may not display heart failure, it is advised that physicians assess the cardiovascular health of the patient before long-term use.

α 1A -AR Blockers May Have Adverse Ocular Effects
Another adverse effect of the long-term use of α 1 -AR antagonists is intraoperative floppy iris syndrome (IFIS), that increases serious complications and is characterized by a poor pupillary response, iris billowing, and prolapse during cataract surgery [194]. α 1 -ARs, and particularly the α 1A -AR subtype, regulates the dilator smooth muscle of the iris [195,196], intraocular pressure [197,198], and the extracellular matrix and metabolic functions in human retinal pigment epithelium cells [199]. Tamsulosin has been identified to causing IFIS among BPH patients, with risks increased up to forty times more compared to other α 1 -AR antagonists and causing severe IFIS [200][201][202][203][204], but other non-selective α 1 -AR antagonists can also cause it. A large meta-analysis of over 6000 cases using various α 1 -AR antagonists indicate that most α 1 -AR blockers associate with a higher risk of IFIS [205]. With the increasing prevalence of both BPH and cataracts in the aging population, it is recommended that tamsulosin use is stopped 2 weeks before cataract surgery or is replaced by another α 1 -AR blocker.

Summary
The use of α 1 -AR agonists to potentially treat heart failure, cardiac ischemia, Alzheimer's disease, and other dementias are targeted to the α 1A -AR subtype. However, all of these studies are preclinical in cell lines and mouse models or in initial clinical trials and it is not currently recommended to use these agents for non-approved use. Current development of positive allosteric modulators would be the choice as first-in-class therapeutics to avoid issues with increasing blood pressure to reduce other adverse side effects. The use of non-selective α 1 -AR antagonists of the quinazoline class to treat severe COVID-19/SARS, PTSD, and neurodegenerative disorders, such as Parkinson's disease and ALS, have extensive evidence of efficacy in many clinical trials. However, the mechanism of action may be non-α 1 -AR mediated. Counterindications for α 1 -AR blockers are focused on those with established heart disease. Future clinical studies and larger, randomized, cross-over trials are required before drawing firmer conclusions about the counterindications of tamsulosin or other α 1A -AR selective blockers.